4-(monoalkylamino)benzonitriles useful as anti-atherosclerotic agents

ABSTRACT

This disclosure describes novel 4-(monoalkylamino)benzonitriles and 5-[4-(monoalkylamino)phenyl]tetrazoles and homologs thereof useful as hypolipidemic and anti-atherosclerotic agents.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds;4-(monoalkylamino)benzonitriles,5-[4-(monoalkylamino)phenyl]-tetrazoles, homologs, derivatives and saltsthereof; which may be represented by the following structural formula:##STR1## wherein R₁ is a straight chain or branched alkyl group of theformula C_(n) H_(2n+1) wherein n is an integer from 8 to 19, inclusive;R₂ is hydrogen or a group convertible in vivo thereinto such as methyl,ethyl, carboxylmethyl, lower alkanoyl (C₁ -C₆), succinyl, 1-(sodiumsulfo)lower alkyl, 1-(sodium sulfo)polyhydroxyalkyl or 1,3-bis(sodiumsulfo)-aralkyl; m is 0, 1 or 2 with the proviso that when Z is cyanothen m may not be zero; and Z is selected from the group consisting ofcyano and 5-tetrazolyl.

A preferred embodiment of this invention consists of those compounds inwhich n is an integer from 14 to 19, inclusive, and R is hydrogen;either in the free or derivatized state, namely those of the structuralformula: ##STR2## wherein n is 14-19, and m and z are as hereinabovedefined.

A more preferred embodiment of this invention consists of thosecompounds in which n is an integer from 14 to 19, inclusive, and R₂ ishydrogen; either in the free or derivatized state, namely those of thestructural formula: ##STR3## wherein m and Z are as defined hereinabove.

The straight chain or normal alkyl groups for the substituent R may be,for example, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and nonadecyl.Suitable branched alkyl groups for the substituent R₁ may be, forexample, 1-methylpentadecyl, 1-ethyltetradecyl, 1-heptylnonyl,2-ethyldodecyl, 1,4-diethyloctyl, 11-methyldodecyl, 5,5-dimethylhexyl,4,8,12-trimethyltridecyl, 2,4,6,8-tetramethylnonyl,1,4-dimethyl-1-ethylhexyl, 15-methylhexadecyl, 13,13-dimethyltetradecyl,15,15-dimethylhexadecyl, and the like.

The invention also pertains to novel compositions of matter useful asanti-atherosclerotic agents and to methods of melioratingatherosclerosis by counteracting hyperlipemia and arterial plaqueformation in mammals therewith; the active ingredients of saidcompositions of matter being the novel benzonitriles andphenyltetrazoles and homologs of the present invention thereof in theunderivatized form or in the form of a pharmaceutically acceptable saltwith an inorganic or organic acid. The invention also contemplates amethod for lowering serum lipids and for meliorating atherosclerosis inmammals by the administration of said nitriles and tetrazoles.

BACKGROUND OF THE INVENTION

Considerable effort has been directed in recent years to obtainsubstances useful in counteracting the consequences of hyperlipidemia, acondition involving elevated cholesterol, phospholipid and/ortriglyceride levels in the blood, and of hyperlipoproteinemia, involvingan imbalance of the lipoproteins. The most serious condition associatedwith hyperlipidemia and hyperlipoproteinemia is atherosclerosis, a formof arteriosclerosis characterized by lipid accumulation and thickeningof the walls of both medium-sized and large arteries such as the aorta.Their walls are thereby weakened and the elasticity and effectiveinternal size of the arteries decreased. Atherosclerosis, the mostcommon cause of coronary artery disease, is of great medical importancesince it tends to occlude those arteries supplying blood to the heartmuscles and brain, thereby producing permanent damage to these organs.Such damage may lead to ischemic heart disease, congestive heartfailure, life-threatening arrhythmias, senility, or stroke. Involvementof leg arteries may lead to gangrene and loss of the limb. It has beenknown for more than 100 years that cholesterol is a major component ofatherosclerotic lesions or plaques. Investigators have been trying todetermine the role of cholesterol in their initiation and developmentand also, most importantly, whether lesion formation can be prevented orreversed and enlargement of lesions be slowed or stopped. The earliestlesions are now known to be fatty streaks, largely of cholesterol, whichoften progress in stages to plaques containing cellular, fibrous andcalcified material in addition to the lipids.

The evidence that hyperlipidemia is one of the factors involved incoronary heart disease is very impressive. A most important studycarried out in Framingham, Mass. (Gordon & Verter, 1969) in over 5,000persons for more than 12 years established a correlation between highconcentrations of blood cholesterol and increased risk of heart attack.Although the causes of coronary artery disease are multiple, one of theconstant factors has been the elevated concentration of lipids in theblood plasma. A combined elevation of cholesterol and triglycerides hasbeen shown (Carlson & Bottiger, 1972) to carry the highest risk ofcoronary heart disease. The majority of patients with ischemic heartdisease or peripheral vascular disease were found to havehyperlipoproteinemia, involving very low-density and/or low-densitylippoproteins (Lewis et al. 1974).

The reason for most treatment of hyperlipidemia or hyperlipoproteinemiais for arresting, reversing or preventing atherosclerosis. In the past,attempts have been made to lower the levels of cholesterol,phospholipids, and triglycerides in the blood by the oral feeding ofvarious substances which have been generally referred to in the art ashypolipidemic agents or hypocholesteremic adjuvants. Typical of suchsubstances are lecithin, pectin, cottonseed oil, and the mucilaginoussubstances listed in U.S. Pat. No. 3,148,144. In addition, severalsynthetic hypolipidemic agents are now available, namely, clofibrate,D-thyroxine, cholestyramine and nicotinic acid [(Levy & Frederickson,Postgraduate Medicine 47, 130 (1970)]. Clofibrate has the undesirableside-effect of causing hypertrophy of the liver in some patients.

The development of agents capable of reducing elevated blood lipids andof favorably altering blood-lipoprotein patterns is considered bymedical authorities to be extremely important for the treatment andprevention of atherosclerosis. Orally active agents are required sincepatients usually take them for a number of years.

DETAILED DESCRIPTION OF THE INVENTION

U.S. Pat. No. 3,868,416 discloses and claims certain4-monoalkylaminobenzoic acid esters, pharmaceutically acceptable saltsthereof, pharmaceutical compositions therewith and a method of loweringserum lipid levels in mammals therewith. No prior art is known whichdiscloses 4-(monoalkylamino)benzonitriles or5-[4-(monoalkylamino)phenyl]-tetrazoles and derivatives and saltsthereof of this invention and no hypolipidemic activity has beenreported in the literature for these compounds, and they are differentin structure from other hypolipidemic agents. The compounds of thisinvention lower serum-lipid concentrations and also minimize atheromaformation in the aorta. These 4-(monoalkylamino)nitriles and tetrazolesprovide the oral administration required of hypolipidemic agents, whichpatients usually take for many years. The anti-atherogenic activity ofthe alkylaminobenzoic acids mentioned above have been announced;Abstract No. 27, American Oil Chemists Society, 67th Meeting, NewOrleans, April 21-24, 1976; Federation Proceedings 36, Abstract No. 4706(1977).

We have now found that members of this class of compounds can safely andeffectively lower both serum sterols and triglycerides in warm-bloodedanimals. Such actions on serum lipid components are considered to bevery useful in the treatment of atherosclerosis, especially in contrastto available drugs whose action is much more limited. For some time ithas been considered desirable to lower serum lipid levels and to correctlipoprotein imbalance in mammals as a preventive measure againstatherosclerosis. The compounds of the present invention do not act byblocking late stages of cholesterol biosynthesis and thus do not produceaccumulation of intermediates such as desmosterol, as equallyundesirable as cholesterol itself. Compounds with the combination oftherapeutically favorable characteristics possessed by those of thepresent invention can be safely administered to warm-blooded mammals forthe treatment of hyperlipidemic and atherosclerotic states found inpatients with or prone to heart attacks, to peripheral or cerebralvascular disease, and to stroke.

The 4-(monoalkylamino)benzonitriles,5-[4-(monoalkylamino)phenyl]tetrazoles, and homologs thereof of thepresent invention are, in general, crystalline solids havingcharacteristic melting points and spectral characteristics. They aresoluble in organic solvents such as lower alkanols, chloroform, benzene,dimethylformamide, and the like, but are generally insoluble in water.Also, the novel nitriles of the present invention are useful asintermediates for the preparation of the novel tetrazoles of the presentinvention.

The novel compounds of the present invention form non-toxicacid-addition salts with a variety of pharmacologically acceptableinorganic salt-forming reagents. Thus, acid-addition salts, formed byadmixture of the organic free base with one or more equivalents of anacid, suitably in a neutral solvent, are formed with such acids assulfuric, phosphoric hydrochloric, hydrobromic, and the like. Theacid-addition salts of the present invention are, in general,crystalline solids, relatively soluble in water, methanol and ethanolbut relatively insoluble in non-polar organic solvents such as diethylether, benzene, toluene, and the like. In addition, the tetrazole ringcan form cationic salts with bases such as the alkali metal hydroxides.

The free nitriles and tetrazoles of this invention may be preparedgenerally as follows. p-Aminobenzonitrile in an organic solvent such ashexamethylphosphoramide is heated with an alkyl (C₈₋₁₉) bromide at atemperature of 80°-130° C. for 8-24 hours, cooling the mixture, addingwater, and isolating the product therefrom. The nitriles may be purifiedby recrystallization from a solvent pair such as ether-hexanes. Theacetonitriles are prepared accordingly by employingp-aminophenylacetonitrile at 50°-80° C.; similarly, the β-propionitrilesfrom β-(aminophenyl)propionitrile. These alkylaminonitriles are alsoprepared by alkylations employing other alkyl halides, sulfates,tosylates or mesylates with or without solvent at 50°-150° C., using anequivalent of an organic or inorganic base instead of an excess of theaminonitrile as base. Alkylation of the alkali metal salts of4-acylaminobenzonitriles is done similarly. Alternative methods ofpreparation are by reductive alkylation of amino nitriles with suitablecarbonylalkanes and by diborane reduction of alkanoylaminonitriles or ofchloroimides formed therefrom. Amination of 4-fluorobenzonitrile in hotexcess alkylamine as solvent or of 4-bromobenzonitrile and lithiumdiisopropylamide in cold excess alkylamine are additional syntheticprocedures. The nitrile group may be generated from aldehydes or theirderivatives by conversion to oximes and treatment with trifluoroaceticanhydride, followed by alkaline removal of the N-trifluoroacetyl group.The alkylaminonitriles may be similarly prepared from N-alkanoylderivatives with alkali and from N-protected intermediates such asN-t-butyloxycarbonyl derivatives with acid. The nitrile group in theacetonitriles and β-propionitriles may be synthesized from alkylamino(benzoyl and β-phenylethyl) halides, etc. and alkali cyanides in polarsolvents at 40°-120° C. employing N-protecting groups when desired.

The 5-[p-alkyl(C₈₋₁₉)aminophenyl]tetrazoles are prepared by treating ap-alkyl(C₈₋₁₉)aminobenzonitrile with sodium azide and ammonium chloridein an organic solvent such as dimethylformamide at a temperature of100°-140° C. for 24-28 hours, and then isolating the product therefromafter the addition of water. The5-[p-alkyl(C₈₋₁₉)aminobenzyl]-tetrazoles may be prepared accordingly byemploying a p-alkyl(C₈₋₁₉)aminophenylacetonitrile; and,β-[p-alkyl(C₈₋₁₉)-aminophenyl]propionitriles are converted into the5-β-[p-alkyl(C₈₋₁₉)aminophenyl]ethyltetrazoles. Acetylation ofmonoalkylaminonitriles in pyridine with acetylating agents such asacetic anhydride, acetyl chloride and the like at 20° to 40° C. for 1-24hours provide the N-acetyl derivatives after the addition of water. Theacid-addition salts of the monoalkylaminonitriles may be convenientlyprepared by treatment of the nitrile in a solvent such as diethyl ether,tetrahydrofuran, dimethoxyethane, and the like, with hydrogen chloride,hydrogen bromide and the like at room-temperature for a period of 3-30minutes, and separating the acid-addition salt therefrom.

Certain derivatives ##STR4## of the aminophenyl nitrogen atom are usefulfor providing greater solubility, more uniform and reliable intestinalabsorption, and for a certain degree of modification of the pharmacologyof the compounds of the present invention. Some of these derivatives canbe converted to the corresponding N--H forms by the acidity of thestomach or the alkalinity of the small intestine. Others are convertedby metabolic processes. The methyl and carboxymethyl derivatives and thelike are prepared by the alkylation, reductive alkylation, and acylaminoreduction methods above. Derivatives such as the acetyl and succinylcompounds may be prepared using acetyl chloride, acetic anhydride,succinic anhydride, etc. in the presence of pyridine, triethylamine orthe like at temperatures moderate enough to avoid acylation of the amidemoiety. The 1-(sodium sulfo)-alkyl derivatives are obtained by reactionof the benzonitriles or phenyltetrazoles, or suitable intermediates incertain cases, with sodium bisulfite and an aliphatic aldehyde, apolyhydroxyaldehyde such as glyceraldehyde or glucose, or cinnamaldehydein a mixed organic-aqueous medium. In the case of cinnamaldehyde, thedi-sulfonate salts result from addition of the bisulfite to thecarbon-nitrogen double bond of the anil intermediate as well as to thecarbon-carbon of cinnamaldehyde itself.

The novel compounds of the present invention are not only hypolipidemicagents but also prevent or diminish the formation or enlargement ofarterial plaques in mammals when administered in amounts ranging fromabout one milligram to about 250 mg. per kilogram of body weight perday. A preferred dosage regimen for optimum results would be from about5 mg. to about 100 mg. per kilogram of body weight per day, and suchdosage units are employed that a total of from about 0.35 grams to about7.0 grams of the active compound for a subject of about 70 kg. of bodyweight are administered in a 24-hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. A decided practical advantage of this invention is that theactive compound may be administered conveniently by the oral route. Itis not known how these novel compounds operate in the blood serum and notheory of why these compounds so operate is advanced. It is not intendedthat the present invention should be limited to any particular mechanismof action of lowering serum lipids or of meliorating atherosclerosis, orbe limited to compounds acting by only one mechanism.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2 to about 60%of the weight of the unit. The amount of active ingredient in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 50 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia,, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active ingredients may be incorporated intosustained-release preparations and formulations.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 p-Hexadecylaminobenzonitrile

p-Aminobenzonitrile (11.8 g., 0.1 mole) and 1-bromohexadecane (15.25 g.,0.05 mole) are dissolved in hexamethylphosphoramide (200 ml.) and heatedunder nitrogen in an oil-bath maintained at 120° for 22 hours. Thereaction mixture is cooled to room temperature and water (50 ml.) isadded gradually. The mixture is then chilled in an ice-bath. Theprecipitate is filtered, washed thoroughly with water and dried. It isthen washed repeatedly with hexane and dried; 14.2 g. pale brownishyellow granular solid is obtained as homogeneous product.Crystallization from ether-hexane affords pale yellow prisms, meltingpoint 63°-64° C.

In the above procedure replacement of 1-bromohexadecane with abromoalkane (C₈₋₁₉) provides the following products:

p-octylaminobenzonitrile,

p-nonylaminobenzonitrile,

p-decylaminobenzonitrile,

p-undecylaminobenzonitrile,

p-(1-methylundecyl)aminobenzonitrile,

p-dodecylaminobenzonitrile,

p-tridecylaminobenzonitrile,

p-tetradecylaminobenzonitrile,

p-pentadecylaminobenzonitrile,

p-(14-methylpentadecyl)aminobenzonitrile,

p-heptadecylaminobenzonitrile,

p-octadecylaminobenzonitrile, and

p-nonadecylaminobenzonitrile.

The bromoalkanes include 1-bromo-14-methylpentadecane prepared asfollows:

A solution of 3-methylbutylmagnesium bromide is prepared by treating15.1 g. of 3-methylbutyl bromide with 2.7 g. of magnesium turnings in 50ml. of dry tetrahydrofuran. The resultant Grignard reagent is addeddropwise to a solution of 34.5 g. of 1,11-dibromoundecane and 0.2 g. oflithium copper chloride in 75 ml. of tetrahydrofuran. After 1 hourstirring at -10° C., the solution is evaporated, and the resultant oilis distilled in vacuo to yield the colorless1-bromo-14-methylpentadecane.

EXAMPLE 2 5-(p-Hexadecylaminophenyl)tetrazole

Sodium azide (0.98 g., 0.015 mole) and NH₄ Cl are added to a solution ofp-hexadecylaminobenzonitrile (5.13 g., 0.015 mole) in dimethylformamide.The mixture is stirred and heated in an oil bath maintained at 120° C.for 42 hours. The reaction mixture is cooled and then poured intoice-water with vigorous stirring. The precipitate separated is filtered,washed thoroughly with water and dried. The dry precipitate is washedrepeatedly with ether and dried; 1.7 g. of a pale brown powder isobtained as a homogeneous product, melting point 114°-116° C. (decomp.).

In the above procedure replacement of p-hexadecylaminobenzonitrile withthe p-alkyl(C₈₋₁₉)aminobenzonitrile described in Example 1 provide thefollowing products:

5-(p-octylaminophenyl)tetrazole,

5-(p-nonylaminophenyl)tetrazole,

5-(p-decylaminophenyl)tetrazole,

5-(p-undecylaminophenyl)tetrazole,

5-[p-(1-methylundecyl)aminophenyl]tetrazole,

5-(p-dodecylaminophenyl)tetrazole,

5-(p-tridecylaminophenyl)tetrazole,

5-(p-tetradecylaminophenyl)tetrazole,

5-(p-pentadecylaminophenyl)tetrazole,

5-[p-(14-methylpentadecyl)aminophenyl]tetrazole,

5-(p-heptadecylaminophenyl)tetrazole,

5-(p-octadecylaminophenyl)tetrazole, and

5-(p-nonadecylaminophenyl)tetrazole.

EXAMPLE 3 p-Hexadecylaminophenylacetonitrile

Following the procedure of Example 1 employing p-aminophenylacetonitrileat 60°-80° C. provides the product of the Example.

EXAMPLE 4 p-Alkyl(C₈₋₁₉)aminophenylacetonitrile

Following the procedure of Example 1 employing a bromoalkane (C₈₋₁₉)with p-aminophenylacetonitrile at 60°-80° C. provide the product of theExample.

EXAMPLE 5 β-(p-Hexadecylaminophenyl)propionitrile

Following the procedure of Example 1 employingβ-(p-aminophenyl)propionitrile at 60°-80° C. provides the product of theExample.

EXAMPLE 6 β-(p-Alkyl(C₈₋₁₉)aminophenyl)propionitrile

Following the procedure of Example 1 employing a bromoalkane (C₈₋₁₉)with β-(p-aminophenyl)propionitrile at 60°-80° C. provide the product ofthe Example.

EXAMPLE 7 5-(p-Hexadecylaminobenzyl)tetrazole

Following the procedure of Example 2 employingp-hexadecylaminophenylacetonitrile provides the product of the Example.

EXAMPLE 8 5-(p-Alkyl(C₈₋₁₉)aminobenzyl)tetrazole

Following the procedure of Example 2p-alkyl(C₈₋₁₉)-aminophenylacetonitrile provide the product of theExample.

EXAMPLE 9 5-[β-(p-Hexadecylaminophenyl)ethyl]tetrazole

Following the procedure of Example 2 employingβ-(p-hexadecylaminophenyl)propionitrile provides the product of theExample.

EXAMPLE 10 5-[β-(p-Alkyl(C₈₋₁₉)aminophenyl)ethyl]tetrazole

Following the procedure of Example 2 employingβ-(p-alkyl(C₈₋₁₉)aminophenyl)propionitrile provides the product of theExample.

EXAMPLE 11 N-Acetyl p-Hexadecylaminobenzonitrile

p-Hexadecylaminobenzonitrile (150 mg.) in pyridine (1 ml.) is treatedwith acetic anhydride (0.5 ml.), and the mixture is allowed to stand atroom temperature for 3 hours. It is then poured into water, and theproduct of the Example is collected.

EXAMPLE 12 p-Hexadecylaminobenzonitrile Hydrochloride

Hydrogen chloride is bubbled with stirring into a solution ofp-hexadecylaminobenzonitrile (1.0 g.) in anhydrous diethyl ether (50ml.). Immediately a white precipitate forms, and after several minutesthe product of the Examples is collected and washed with diethyl ether.

EXAMPLE 13

    ______________________________________                                        Preparation of 50 mg. Tablets                                                 Per Tablet              Per 10,000 Tablets                                    ______________________________________                                        0.050 gm.                                                                             Active ingredient    500 gm.                                          0.080 gm.                                                                             Lactose              800 gm.                                          0.010 gm.                                                                             Corn Starch (for mix)                                                                              100 gm.                                          0.008 gm.                                                                             Corn Starch (for paste)                                                                            75 gm.                                           0.148 gm.                   1475 gm.                                          0.002 gm.                    15 gm.                                           0.150 gm.                   1490 gm.                                          ______________________________________                                    

The active ingredient, lactose and corn starch (for mix) are blendedtogether. The corn starch (for paste) is suspended in 600 ml. of waterand heated with stirring to form a paste. This paste is then used togranulate the mixed powders. Additional water is used if necessary. Thewet granules are passed through a No. 8 hand screen and dried at 120° F.The dry granules are then passed through a No. 16 screen. The mixture islubricated with 1% magnesium stearate and compressed into tablets in asuitable tableting machine.

EXAMPLE 14

    ______________________________________                                        Preparation of Oral Suspension                                                Ingredient             Amount                                                 ______________________________________                                        Active ingredient      500      mg.                                           Sorbitol solution (70% N.F.)                                                                         40       ml.                                           Sodium benzoate        150      mg.                                           Saccharin              10       mg.                                           Red dye                10       mg.                                           Cherry flavor          50       mg.                                           Distilled water qs ad  100      ml.                                           ______________________________________                                    

The sorbitol solution is added to 40 ml. of distilled water and theactive ingredient is suspended therein. The saccharin, sodium benzoate,flavor and dye are added and dissolved. The volume is adjusted to 100ml. with distilled water. Each ml. of syrup contains 5 mg. of activeingredient.

I claim:
 1. A compound of the structural formula: ##STR5## wherein R₁ is a straight chain or branched alkyl group of the formula C_(n) H_(2n+1) wherein n is an integer from 8 to 19, inclusive, and m is 1 or 2; and the pharmacologically acceptable acid-addition salts thereof.
 2. The compounds of claim 1 in the form of pharmaceutically acceptable acid-addition salts.
 3. A compound of the structural formula: ##STR6## wherein n is an integer from 14 to 19, inclusive, and m is 1 or 2; and the pharmacologically acceptable acid-addition salts thereof.
 4. A compound of the structural formula: ##STR7## wherein m is 1 or 2 and the pharmacologically acceptable acid-addition salth thereof.
 5. p-(14-Methylpentadecyl)aminobenzonitrile.
 6. p-Hexadecylaminobenzonitrile.
 7. p-Hexadecylaminophenylacetonitrile.
 8. β-(p-Hexadecylaminophenyl)propionitrile.
 9. p-Hexadecylaminobenzonitrile hydrochloride.
 10. The method of inhibiting atherosclerotic lesion development in a mammal comprising administering to said mammal an effective lesion development inhibiting amount of a compound of the formula: ##STR8## wherein R₁ is a straight chain or branched alkyl group of the formula C_(n) H_(2n+1) wherein n is an integer from 8 to 19, inclusive; R₂ is hydrogen, alkyl having up to 3 carbon atoms, 1-(sodium sulfo)alkyl or alkanoyl having up to 6 carbon atoms; m is 0, 1 or 2; and the pharmaceutically acceptable acid-addition salts thereof.
 11. The method of claim 10 wherein said compound is administered to provide a daily dosage of from about one mg. to about 250 mg. per kilogram of body weight of said mammal.
 12. An anti-atherosclerotic composition in dosage unit form useful for preventing or diminishing atherosclerotic lesion formation in mammals comprising from about one mg. to about 250 mg. per kilogram of body weight per daily dosage unit of a compound of the formula: ##STR9## wherein R₁ is a straight chain or branched alkyl group of the formula C_(n) H_(2n+1) wherein n is an integer from 8 to 19, inclusive; R₂ is hydrogen, alkyl having up to 3 carbon atoms, 1-(sodium sulfo)alkyl or alkanoyl having up to 6 carbon atoms; m is 0, 1 or 2, and the pharmaceutically acceptable acid-addition salts thereof; in association with a pharmaceutical carrier.
 13. The method of inducing regression of atherosclerotic lesion development in a mammal comprising administering to said mammal an effective lesion regressive amount of a compound of the formula: ##STR10## wherein R₁ is a straight chain or branched alkyl group of the formula C_(n) H_(2n+1) wherein n is an integer from 8 to 19, inclusive; R₂ is hydrogen, alkyl having up to 3 carbon atoms, 1-(sodium sulfo)alkyl or alkanoyl having up to 6 carbon atoms; m is 0, 1 or 2; and the pharmaceutically acceptable acid-addition salts thereof.
 14. The method of claim 13 wherein said compound is administered to provide a daily dosage of from about one mg. to about 250 mg. per kilogram of body weight of said mammal. 